Alzheimer?s disease (AD) is a complex multifactorial disease with the possible involvement of a number of genes. Although the APOE*4 allele has been identified as a strong susceptibility marker for AD, it is neither necessary nor sufficient to cause the disease. This indicates the involvement of additional genetic factors, which either alone or in conjunction with APOE*4, increase an individual?s risk of developing AD. Recent studies indicate that apolipoprotein D (apoD) is involved in the neurodegenerative as well as neuroregenerative processes. Our novel preliminary immunohistochemical and genetic data also provide strong evidence that apoD is involved in the pathogenesis of AD. The objectives of this study will be achieved by fulfilling the following specific aims: 1) to confirm our preliminary findings that apoD shows different patterns of immunoreactivity between normal and AD brains and that apoD and AD localize in plaques, we will examine several additional brains from normal and AD cases, 2) to examine the functional role of apoD in modifying AP fibril formation and its role in mediation of apoE- regulated A beta fibril formation in vitro, 3) to screen all exons, introns and 5? and 3? regions of the apoD gene by polymerase chain reaction (PCR), HPLC-based Wave DNA Fragment Analysis system and DNA sequencing in 1 00 autopsy confirmed AD cases (50 with APOE*4 and 50 without APOE*4) to identify and characterize genetic variation in the apoD gene. The association of the apoD genetic variation with the risk of AD will be evaluated in two case-control cohorts of U.S. whites and blacks. The proposed immunochemical, functional, molecular and genetic epidemiological studies will enable us to delineate the role of the apoD in the etiology of AD.